Methods and systems for photoacoustic monitoring using indicator dilution

ABSTRACT

A patient monitoring system may provide photoacoustic sensing based on an indicator dilution to determine one or more physiological parameters of a subject. The system may detect an acoustic pressure signal, which may include one or more thermo-dilution responses, one or more hemo-dilution responses, or a combination thereof. For example, a thermo-dilution indicator and/or a hemo-dilution indicator may be used to determine one or more hemodynamic parameters. In a further example, an isotonic indicator and a hypertonic indicator may be used to determine one or more hemodynamic parameters of the subject.

The present disclosure relates to monitoring physiological parameters,and more particularly relates to monitoring physiological parametersusing indicator dilution and photoacoustic analysis.

SUMMARY

A physiological monitoring system may be configured to determine aphysiological parameter of a subject, using photoacoustic analysis and adilution response. The system may include a light source that mayprovide a photonic signal to a first blood vessel site of the subject,which may be, for example, an artery of the subject. The system may alsoinclude an acoustic detector that detects an acoustic pressure signalfrom the first blood vessel site, caused by the absorption of at leastsome of the photonic signal by one or more constituents at the firstblood vessel site.

In some embodiments, a hemo-dilution indicator, thermo-dilutionindicator, or both, may be provided to a blood vessel site of thesubject, which may be, for example, a vein of the subject. The one ormore indicators may include a dye indicator, a saline indicator, or anyother suitable type of indicator. A photoacoustic signal derived fromthe acoustic pressure signal may include one or more responsescorresponding to one or more respective indicators. Based at least inpart on the one or more responses, the system may determine one or morephysiological parameters of the subject. The physiological parametersmay include hemodynamic parameters such as, for example, cardiac output,intrathoracic blood volume, intrathoracic circulatory volume, globalend-diastolic volume, pulmonary circulatory volume, extravascular lungwater, and/or other suitable parameters. In some embodiments, one ormore characteristics may be derived from an acoustic pressure signalsuch as, for example, a value of the acoustic pressure signal, a valueof a signal derived from the acoustic pressure signal such as aphotoacoustic signal, an area under a dilution curve derived from thephotoacoustic signal, a time, or a time difference, and may be used todetermine the one or more physiological parameters.

In some embodiments, an isotonic indicator and a hypertonic indicatormay be provided to the subject at a second blood vessel site, which maybe, for example, a central vein. The photoacoustic signal may include afirst response corresponding to the isotonic indicator and a secondresponse corresponding to the hypertonic indicator. Based at least inpart on the first and second response, the system may determine one ormore physiological parameters of the subject. The physiologicalparameters may include hemodynamic parameters such as, for example,cardiac output and extravascular lung water. In some embodiments, atleast one of the isotonic indicator and the hypertonic indicatorcomprises a dye indicator. In some embodiments, the system may generatea dilution curve, and determine the one or more physiological parametersbased at least in part on the dilution curve.

BRIEF DESCRIPTION OF THE FIGURES

The above and other features of the present disclosure, its nature andvarious advantages will be more apparent upon consideration of thefollowing detailed description, taken in conjunction with theaccompanying drawings in which:

FIG. 1 shows an illustrative physiological monitoring system, inaccordance with some embodiments of the present disclosure;

FIG. 2 is a block diagram of the illustrative physiological monitoringsystem of FIG. 1 coupled to a subject, in accordance with someembodiments of the present disclosure;

FIG. 3 is a block diagram of an illustrative signal processing system,in accordance with some embodiments of the present disclosure;

FIG. 4 shows an illustrative photoacoustic arrangement, in accordancewith some embodiments of the present disclosure;

FIG. 5 shows an illustrative indicator arrangement, in accordance withsome embodiments of the present disclosure;

FIG. 6 shows illustrative dilution curves for isotonic and hypertonicsaline indicators, in accordance with some embodiments of the presentdisclosure;

FIG. 7 shows an illustrative photoacoustic signal, including a responsecorresponding to an isotonic indicator, in accordance with someembodiments of the present disclosure;

FIG. 8 shows an illustrative plot of total hemoglobin concentration asisotonic and hypertonic indicators pass a photoacoustic detection site,in accordance with some embodiments of the present disclosure;

FIG. 9 is a flow diagram of illustrative steps for determining aphysiological parameter from an acoustic pressure signal having anindicator dilution response, in accordance with some embodiments of thepresent disclosure;

FIG. 10 is a flow diagram of illustrative steps for determining aphysiological parameter from an acoustic pressure signal having a firstand a second response, in accordance with some embodiments of thepresent disclosure;

FIG. 11 is a flow diagram of illustrative steps for determining aphysiological parameter from an acoustic pressure signal having a firstand a second response, corresponding to respective hypertonic andisotonic indicators, in accordance with some embodiments of the presentdisclosure; and

FIG. 12 is a flow diagram of illustrative steps for determining aphysiological parameter from an acoustic pressure signal having ahemo-dilution and/or thermo-dilution response, in accordance with someembodiments of the present disclosure.

DETAILED DESCRIPTION OF THE FIGURES

Photoacoustics (or “optoacoustics”) or the photoacoustic effect (or“optoacoustic effect”) refers to the phenomenon in which one or morewavelengths of light are presented to and absorbed by one or moreconstituents of an object, thereby causing an increase in kinetic energyof the one or more constituents, which causes an associated pressureresponse within the object. Particular modulations or pulsing of theincident light, along with measurements of the corresponding pressureresponse in, for example, tissue of the subject, may be used for medicalimaging, physiological parameter determination, or both. For example,the concentration of a constituent, such as hemoglobin (e.g.,oxygenated, deoxygenated and/or total hemoglobin) may be determinedusing photoacoustic analysis. In a further example, one or morehemodynamic parameters such as cardiac output, intrathoracic bloodvolume, intrathoracic circulatory volume, global end-diastolic volume,pulmonary circulatory volume, extravascular lung water, and/or any othersuitable hemodynamic parameters may be determined using photoacousticanalysis and indicator dilution techniques.

A photoacoustic system may include a photoacoustic sensor that is placedat a site on a subject, typically the wrist, palm, neck, forehead,temple, or anywhere an artery or vessel is accessible noninvasively. Insome embodiments, the photoacoustic techniques described herein are usedto monitor large blood vessels, such as a major artery or vein which maybe near the heart (e.g., the carotid or radial arteries or the jugularvein). The photoacoustic system may use a light source, and any suitablelight guides (e.g., fiber optics), to pass light through the subject'stissue, or a combination of tissue thereof (e.g., organs), and anacoustic detector to sense the pressure response of the tissue inducedby the light absorption by a blood vessel. Tissue may include muscle,fat, blood, blood vessels, and/or any other suitable tissue types. Insome embodiments, the light source may be a laser or laser diode,operated in pulsed or continuous wave (CW) mode. In some embodiments,the acoustic detector may be an ultrasound detector, which may besuitable to detect pressure fluctuations arising from the constituent'sabsorption of the incident light of the light source.

In some embodiments, the light from the light source may be focused,shaped, or otherwise spatially modulated to illuminate a particularregion of interest. In some arrangements, photoacoustic monitoring mayallow relatively higher spatial resolution than line of sight opticaltechniques (e.g., path integrated absorption measurements). The enhancedspatial resolution of the photoacoustic technique may allow for imaging,scalar field mapping, and other spatially resolved results, in 1, 2, or3 spatial dimensions. The acoustic response to the photonic excitationmay radiate from the illuminated region of interest, and accordingly maybe detected at multiple positions.

The photoacoustic system may measure the pressure response that isreceived at the acoustic sensor as a function of time. The photoacousticsystem may also include sensors at multiple locations. A signalrepresenting pressure versus time or a mathematical manipulation of thissignal (e.g., a scaled version thereof, etc.) may be referred to as thephotoacoustic (PA) signal. The PA signal may be derived from a detectedacoustic pressure signal by selecting a suitable subset of points of anacoustic pressure signal. The PA signal may be used to calculate any ofa number of physiological parameters, including a concentration of ablood constituent (e.g., hemoglobin), at a particular spatial location.In some embodiments, PA signals from multiple spatial locations may beused to construct an image (e.g., imaging blood vessels) or a scalarfield (e.g., a hemoglobin concentration field). In some embodiments, anindicator such as, for example, a dye or saline solution may beintroduced into the blood stream of a subject, and the PA system may beused to determine a concentration of a blood constituent, aconcentration of an indicator, a relative temperature difference, anysuitable characteristic of an indicator dilution response, any suitablehemodynamic parameters derived thereof, any other suitable parameter, orany combination thereof.

In some applications, the light passed through the tissue is selected tobe of one or more wavelengths that are absorbed by the constituent in anamount representative of the amount of the constituent present in thetissue. The absorption of light passed through the tissue varies inaccordance with the amount of the constituent in the tissue. Forexample, Red and/or infrared (IR) wavelengths may be used because highlyoxygenated blood will absorb relatively less Red light and more IR lightthan blood with a lower oxygen saturation.

Any suitable light source may be used, and characteristics of the lightprovided by the light source may be controlled in any suitable manner.In some embodiments, a pulsed light source may be used to providerelatively short-duration pulses (e.g., nanosecond pulses) of light tothe region of interest. Accordingly, the use of a pulse light source mayresult in a relatively broadband acoustic response (e.g., depending onthe pulse duration). The use of a pulsed light source will be referredto herein as the “Time Domain Photoacoustic” (TD-PA) technique. Aconvenient starting point for analyzing a TD-PA signal is given by Eq.1:p(z)=Γμ_(a)φ(z)  1)under conditions where the irradiation time is small compared to thecharacteristic thermal diffusion time determined by the properties ofthe specific tissue type. Referring to Eq. 1, p(z) is the PA signal(indicative of the maximum induced pressure rise, derived from anacoustic pressure signal) at spatial location z indicative of acousticpressure, Γ is the dimensionless Grüneisen parameter of the tissue,μ_(a) is the effective absorption coefficient of the tissue (orconstituent thereof) to the incident light, and φ(z) is the opticalfluence at spatial location z. The Grüneisen parameter is adimensionless description of thermoelastic effects, and may beillustratively formulated by Eq. 2:

$\begin{matrix}{\Gamma = \frac{\beta\; c_{a}^{2}}{C_{P}}} & (2)\end{matrix}$where C_(a) is the speed of sound in the tissue, β is the isobaricvolume thermal expansion coefficient, and C_(P) is the specific heat atconstant pressure. In some circumstances, the optical fluence, atspatial location z (within the subject's tissue) of interest may bedependent upon the light source, the location itself (e.g., the depth),and optical properties (e.g., scattering coefficient, absorptioncoefficient, or other properties) along the optical path. For example,Eq. 3 provides an illustrative expression for the attenuated opticalfluence at a depth z:φ(z)=φ₀ e ^(−μ) ^(eff) ^(z)  (3)where φ₀ is the optical fluence from the light source incident at thetissue surface, z is the path length (i.e., the depth into the tissue inthis example), and μ_(eff) is an effective attenuation coefficient ofthe tissue along the path length in the tissue in this example.

In some embodiments, a more detailed expression or model may be usedrather than the illustrative expression of Eq. 3. In some embodiments,the actual pressure encountered by an acoustic detector may beproportional to Eq. 1, as the focal distance and solid angle (e.g., facearea) of the detector may affect the actual measured PA signal. In someembodiments, an ultrasound detector positioned relatively farther awayfrom the region of interest, will encounter a relatively smalleracoustic pressure. For example, the peak acoustic pressure signalreceived at a circular area A_(d) positioned at a distance R from theilluminated region of interest may be given by Eq. 4:p _(d) =p(z)f(r _(s) ,R,A _(d))  (4)where r_(s) is the radius of the illuminated region of interest (andtypically r_(s)<R), and p(z) is given by Eq. 1. In some embodiments, thedetected acoustic pressure amplitude may decrease as the distance Rincreases (e.g., for a spherical acoustic wave).

In some embodiments, a modulated CW light source may be used to providea photonic excitation of a tissue constituent to cause a photoacousticresponse in the tissue. The CW light source may be intensity modulatedat one or more characteristic frequencies. The use of a CW light source,intensity modulated at one or more frequencies, will be referred toherein as the “Frequency Domain Photoacoustic” (FD-PA) technique.Although the FD-PA technique may include using frequency domainanalysis, the technique may use time domain analysis, wavelet domainanalysis, or any other suitable analysis, or any combination thereof.Accordingly, the term “frequency domain” as used in “FD-PA” refers tothe frequency modulation of the photonic signal, and not to the type ofanalysis used to process the photoacoustic response.

Under some conditions, the acoustic pressure p(R,t) at detector positionR at time t, may be shown illustratively by Eq. 5:

$\begin{matrix}{{\left. {p\left( {R,t} \right)} \right.\sim\frac{p_{0}\left( {r_{0},\omega} \right)}{R}}{\mathbb{e}}^{- {{\mathbb{i}\omega}{({t - \tau})}}}} & (5)\end{matrix}$where r₀ is the position of the illuminated region of interest, ω is theangular frequency of the acoustic wave (caused by modulation of thephotonic signal at frequency ω), R is the distance between theilluminated region of interest and the detector, and τ is the traveltime delay of the wave equal to R/c_(a), where c_(a) is the speed ofsound in the tissue. The FD-PA spectrum p₀(r₀,ω) of acoustic waves isshown illustratively by Eq. 6:

$\begin{matrix}{{p_{0}\left( {r_{0},\omega} \right)} = \frac{{\Gamma\mu}_{a}{\phi\left( r_{0} \right)}}{2\left( {{\mu_{a}c_{a}} - {\mathbb{i}\omega}} \right)}} & (6)\end{matrix}$where μ_(a)c_(a) represents a characteristic frequency (andcorresponding time scale) of the tissue.

In some embodiments, a FD-PA system may temporally vary thecharacteristic modulation frequency of the CW light source, andaccordingly the characteristic frequency of the associated acousticresponse. For example, the FD-PA system may use linear frequencymodulation (LFM), either increasing or decreasing with time, which issometimes referred to as “chirp” signal modulation. Shown in Eq. 7 is anillustrative expression for a sinusoidal chirp signal r(t):

$\begin{matrix}{{r(t)} = {\sin\left( {t\left( {\omega_{0} + {\frac{b}{2}t}} \right)} \right)}} & (7)\end{matrix}$where ω₀ is a starting angular frequency, and b is the angular frequencyscan rate. Any suitable range of frequencies (and corresponding angularfrequencies) may be used for modulation such as, for example, 1-5 MHz,200-800 kHz, or other suitable range, in accordance with the presentdisclosure. In some embodiments, signals having a characteristicfrequency that changes as a nonlinear function of time may be used. Anysuitable technique, or combination of techniques thereof, may be used toanalyze a FD acoustic pressure signal. Two such exemplary techniques, acorrelation technique and a heterodyne mixing technique, will bediscussed below as illustrative examples.

In some embodiments, the correlation technique may be used to determinethe travel time delay of the FD-PA signal. In some embodiments, amatched filtering technique may be used to process a PA signal. As shownin Eq. 8:

$\begin{matrix}{{B_{s}\left( {t - \tau} \right)} = {\frac{1}{2\pi}{\int_{- \infty}^{\infty}{{H(\omega)}{S(\omega)}{\mathbb{e}}^{{\mathbb{i}\omega}\; t}{\mathbb{d}\omega}}}}} & (8)\end{matrix}$Fourier transforms (and inverse transforms) are used to calculate thefilter output B_(S)(t−T), in which H(ω) is the filter frequencyresponse, S(ω) is the Fourier transform of the PA signal s(t), and T isthe phase difference between the filter and signal. In somecircumstances, the filter output of expression of Eq. 8 may beequivalent to an autocorrelation function. Shown in Eq. 9:

$\begin{matrix}{{S(\omega)} = {\frac{1}{2\pi}{\int_{- \infty}^{\infty}{{s(t)}{\mathbb{e}}^{{- {\mathbb{i}\omega}}\; t}{\mathbb{d}t}}}}} & (9)\end{matrix}$is an expression for computing the Fourier transform S(ω) of the PAsignal s(t). Shown in Eq. 10:H(ω)=S*(ω)e ^(−iωτ)  (10)is an expression for computing the filter frequency response H(ω) basedon the Fourier transform of the PA signal s(t), in which S*(ω) is thecomplex conjugate of S(ω). It can be observed that the filter frequencyresponse of Eq. 10 requires the frequency character of the PA signal beknown beforehand to determine the frequency response of the filter. Insome embodiments, as shown by Eq. 11:

$\begin{matrix}{{B(t)} = {\int_{- \infty}^{\infty}{{r\left( t^{\prime} \right)}{s\left( {t + t^{\prime}} \right)}{\mathbb{d}t^{\prime}}}}} & (11)\end{matrix}$the known modulation signal r(t) may be used for generating across-correlation with the PA signal. The cross-correlation output B(t)of Eq. 11 is expected to exhibit a peak at a time t equal to theacoustic signal travel time τ. Assuming that the temperature responseand resulting acoustic response follow the illumination modulation(e.g., are coherent), Eq. 11 may allow calculation of the time delay,depth information, or both.

In some embodiments, the heterodyne mixing technique may be used todetermine the travel time delay of the FD-PA signal. The FD-PA signal,as described above, may have similar frequency character as themodulation signal (e.g., coherence), albeit shifted in time due to thetravel time of the acoustic signal. For example, a chirp modulationsignal, such as r(t) of Eq. 7, may be used to modulate a CW lightsource. Heterodyne mixing uses the trigonometric identity of thefollowing Eq. 12:sin(A)sin(B)=½[cos(A−B)−cos(A+B)]  (12)which shows that two signals may be combined by multiplication to giveperiodic signals at two distinct frequencies (i.e., the sum and thedifference of the original frequencies). If the result is passed througha low-pass filter to remove the higher frequency term (i.e., the sum),the resulting filtered, frequency shifted signal may be analyzed. Forexample, Eq. 13 shows a heterodyne signal L(t):

$\begin{matrix}{{L(t)} = {{\left\langle {{r(t)}{s(t)}} \right\rangle \cong \left\langle {{{Kr}(t)}{r\left( {t - \frac{R}{c_{a}}} \right)}} \right\rangle} = {\frac{1}{2}K\;{\cos\left( {{\frac{R}{c_{a}}{bt}} + \theta} \right)}}}} & (13)\end{matrix}$calculated by low-pass filtering (shown by angle brackets) the productof modulation signal r(t) and PA signal s(t). If the PA signal isassumed to be equivalent to the modulation signal, with a time lagR/c_(a) due to travel time of the acoustic wave and amplitude scaling K,then a convenient approximation of Eq. 13 may be made, giving therightmost expression of Eq. 13. Analysis of the rightmost expression ofEq. 13 may provide depth information, travel time, or both. For example,a fast Fourier transform (FFT) may be performed on the heterodynesignal, and the frequency associated with the highest peak may beconsidered equivalent to time lag Rb/c_(a). Assuming that the frequencyscan rate b and the speed of sound c_(a) are known, the depth R may beestimated.

In some embodiments, a photoacoustic signal may be used with Eq. 1 todetermine an absorption coefficient μ_(a). When a suitable light sourceis used (e.g., a photonic signal at 905 nm), tHb may be determined basedon the value of the absorption coefficient and one or more pre-definedparameters. In some embodiments, a photonic signal may include lighthave two different wavelengths (e.g., one of which may be 905 nm), andblood oxygen saturation may be determined based on photoacoustic signalscorresponding to the each wavelength of the photonic signal. In someembodiments, a light source may provide a photonic signal includinglight having a wavelength at an isobestic point where light absorptionof oxy and de-oxy hemoglobin are substantially equal (e.g., at about 808nm).

FIG. 1 is a perspective view of an embodiment of a physiologicalmonitoring system 10. System 10 may include sensor unit 12 and monitor14. In some embodiments, sensor unit 12 may be part of a photoacousticmonitor or imaging system. Sensor unit 12 may include a light source 16for emitting light at one or more wavelengths, which may but need notcorrespond to visible light, into a subject's tissue. Light source 16may provide a photonic signal including any suitable electromagneticradiation such as, for example, a radio wave, a microwave wave, aninfrared wave, a visible light wave, ultraviolet wave, any othersuitable light wave, or any combination thereof. A detector 18 may alsobe provided in sensor unit 12 for detecting the acoustic (e.g.,ultrasound) response that travels through the subject's tissue. Anysuitable physical configuration of light source 16 and detector 18 maybe used. In an embodiment, sensor unit 12 may include multiple lightsources and/or acoustic detectors, which may be spaced apart. System 10may also include one or more additional sensor units (not shown) thatmay take the form of any of the embodiments described herein withreference to sensor unit 12. An additional sensor unit may be the sametype of sensor unit as sensor unit 12, or a different sensor unit typethan sensor unit 12 (e.g., a photoplethysmograph sensor). Multiplesensor units may be capable of being positioned at two differentlocations on a subject's body.

In some embodiments, system 10 may include two or more sensors forming asensor array in lieu of either or both of the sensor units. In someembodiments, a sensor array may include multiple light sources,detectors, or both. It will be understood that any type of sensor,including any type of physiological sensor, may be used in one or moresensor units in accordance with the systems and techniques disclosedherein. It is understood that any number of sensors measuring any numberof physiological signals may be used to determine physiologicalinformation in accordance with the techniques described herein.

In some embodiments, sensor unit 12 may be connected to and draw itspower from monitor 14 as shown. In another embodiment, the sensor may bewirelessly connected to monitor 14 and include its own battery orsimilar power supply (not shown). Monitor 14 may be configured tocalculate physiological parameters based at least in part on datarelating to light emission and acoustic detection received from one ormore sensor units such as sensor unit 12. For example, monitor 14 may beconfigured to determine cardiac output, intrathoracic blood volume,intrathoracic circulatory volume, global end-diastolic volume, pulmonarycirculatory volume, extravascular lung water, any other suitablehemodynamic parameters, or any combination thereof. Further, monitor 14may be configured to determine pulse rate, blood pressure, blood oxygensaturation (e.g., arterial, venous, or both), hemoglobin concentration(e.g., oxygenated, deoxygenated, and/or total), any other suitablephysiological parameters, or any combination thereof. In someembodiments, calculations may be performed on the sensor units or anintermediate device and the result of the calculations may be passed tomonitor 14. Further, monitor 14 may include a display 20 configured todisplay the physiological parameters or other information about thesystem. In the embodiment shown, monitor 14 may also include a speaker22 to provide an audible sound that may be used in various otherembodiments, such as for example, sounding an audible alarm in the eventthat a subject's physiological parameters are not within a predefinednormal range. In some embodiments, the system 10 includes a stand-alonemonitor in communication with the monitor 14 via a cable or a wirelessnetwork link.

In some embodiments, sensor unit 12 may be communicatively coupled tomonitor 14 via a cable 24. Cable 24 may include electronic conductors(e.g., wires for transmitting electronic signals from detector 18),optical fibers (e.g., multi-mode or single-mode fibers for transmittingemitted light from light source 16), any other suitable components, anysuitable insulation or sheathing, or any combination thereof. In someembodiments, a wireless transmission device (not shown) or the like maybe used instead of or in addition to cable 24. Monitor 14 may include asensor interface configured to receive physiological signals from sensorunit 12, provide signals and power to sensor unit 12, or otherwisecommunicate with sensor unit 12. The sensor interface may include anysuitable hardware, software, or both, which may be allow communicationbetween monitor 14 and sensor unit 12.

In the illustrated embodiment, system 10 includes a multi-parameterphysiological monitor 26. The monitor 26 may include a cathode ray tubedisplay, a flat panel display (as shown) such as a liquid crystaldisplay (LCD) or a plasma display, or may include any other type ofmonitor now known or later developed. Multi-parameter physiologicalmonitor 26 may be configured to calculate physiological parameters andto provide a display 28 for information from monitor 14 and from othermedical monitoring devices or systems (not shown). For example,multi-parameter physiological monitor 26 may be configured to display anestimate of a subject's extravascular lung water, cardiac output, andhemoglobin concentration generated by monitor 14. Multi-parameterphysiological monitor 26 may include a speaker 30.

Monitor 14 may be communicatively coupled to multi-parameterphysiological monitor 26 via a cable 32 or 34 that is coupled to asensor input port or a digital communications port, respectively and/ormay communicate wirelessly (not shown). In addition, monitor 14 and/ormulti-parameter physiological monitor 26 may be coupled to a network toenable the sharing of information with servers or other workstations(not shown). Monitor 14 may be powered by a battery (not shown) or by aconventional power source such as a wall outlet.

FIG. 2 is a block diagram of a physiological monitoring system, such asphysiological monitoring system 10 of FIG. 1, which may be coupled to asubject 40 in accordance with an embodiment. Certain illustrativecomponents of sensor unit 12 and monitor 14 are illustrated in FIG. 2.

Sensor unit 12 may include light source 16, detector 18, and encoder 42.In some embodiments, light source 16 may be configured to emit one ormore wavelengths of light (e.g., visible, infrared) into a subject'stissue 40. Hence, light source 16 may provide Red light, IR light, anyother suitable light, or any combination thereof, that may be used tocalculate the subject's physiological parameters. In some embodiments, aRed wavelength may be between about 600 nm and about 700 nm. In someembodiments, an IR wavelength may be between about 800 nm and about 1000nm. In embodiments where a sensor array is used in place of a singlesensor, each sensor may be configured to provide light of a singlewavelength. For example, a first sensor may emit only a Red light whilea second may emit only an IR light. In a further example, thewavelengths of light used may be selected based on the specific locationof the sensor. In a further example, one or more sensors may providelight at about 730 nm, about 810 nm, and/or about 900 nm.

It will be understood that, as used herein, the term “light” may referto energy produced by electromagnetic radiation sources. Light may be ofany suitable wavelength and intensity, and modulations thereof, in anysuitable shape and direction. Detector 18 may be chosen to bespecifically sensitive to the acoustic response of the subject's tissuearising from use of light source 16. It will also be understood that, asused herein, the “acoustic response” shall refer to pressure and changesthereof caused by a thermal response (e.g., expansion and contraction)of tissue to light absorption by the tissue or constituent thereof.

In some embodiments, detector 18 may be configured to detect theacoustic response of tissue to the photonic excitation caused by thelight source. In some embodiments, detector 18 may be a piezoelectrictransducer which may detect force and pressure and output an electricalsignal via the piezoelectric effect. In some embodiments, detector 18may be a Faby-Pérot interferometer, or etalon. For example, a thin film(e.g., composed of a polymer) may be irradiated with reference light,which may be internally reflected by the film. Pressure fluctuations maymodulate the film thickness, thus causing changes in the reference lightreflection which may be measured and correlated with the acousticpressure. In some embodiments, detector 18 may be configured orotherwise tuned to detect acoustic response in a particular frequencyrange. Detector 18 may convert the acoustic pressure signal into anelectrical signal (e.g., using a piezoelectric material, photodetectorof a Faby-Pérot interferometer, or other suitable device). Afterconverting the received acoustic pressure signal to an electrical,optical, and/or wireless signal, detector 18 may send the signal tomonitor 14, where physiological parameters may be calculated based onthe photoacoustic activity within the subject's tissue 40. The signaloutputted from detector 18 and/or a pre-processed signal derivedthereof, will be referred to herein as a photoacoustic signal.

In some embodiments, encoder 42 may contain information about sensorunit 12, such as what type of sensor it is (e.g., where the sensor isintended to be placed on a subject), the wavelength(s) of light emittedby light source 16, the intensity of light emitted by light source 16(e.g., output wattage or Joules), the mode of light source 16 (e.g.,pulsed versus CW), any other suitable information, or any combinationthereof. This information may be used by monitor 14 to selectappropriate algorithms, lookup tables and/or calibration coefficientsstored in monitor 14 for calculating the subject's physiologicalparameters.

Encoder 42 may contain information specific to subject 40, such as, forexample, the subject's age, weight, and diagnosis. This informationabout a subject's characteristics may allow monitor 14 to determine, forexample, subject-specific threshold ranges in which the subject'sphysiological parameter measurements should fall and to enable ordisable additional physiological parameter algorithms. Encoder 42 may,for instance, be a coded resistor that stores values corresponding tothe type of sensor unit 12 or the type of each sensor in the sensorarray, the wavelengths of light emitted by light source 16 on eachsensor of the sensor array, and/or the subject's characteristics. Insome embodiments, encoder 42 may include a memory on which one or moreof the following information may be stored for communication to monitor14: the type of the sensor unit 12; the wavelengths of light emitted bylight source 16; the particular acoustic range that each sensor in thesensor array is monitoring; the particular acoustic spectralcharacteristics of a detector; a signal threshold for each sensor in thesensor array; any other suitable information; or any combinationthereof.

In some embodiments, signals from detector 18 and encoder 42 may betransmitted to monitor 14. In the embodiment shown, monitor 14 mayinclude a general-purpose microprocessor 48 connected to an internal bus50. Microprocessor 48 may be adapted to execute software, which mayinclude an operating system and one or more applications, as part ofperforming the functions described herein. Also connected to bus 50 maybe a read-only memory (ROM) 52, a random access memory (RAM) 54, userinputs 56, display 20, and speaker 22.

RAM 54 and ROM 52 are illustrated by way of example, and not limitation.Any suitable computer-readable media may be used in the system for datastorage. Computer-readable media are capable of storing information thatcan be interpreted by microprocessor 48. This information may be data ormay take the form of computer-executable instructions, such as softwareapplications, that cause the microprocessor to perform certain functionsand/or computer-implemented methods. Depending on the embodiment, suchcomputer-readable media may include computer storage media andcommunication media. Computer storage media may include volatile andnon-volatile, removable and non-removable media implemented in anymethod or technology for storage of information such ascomputer-readable instructions, data structures, program modules orother data. Computer storage media may include, but is not limited to,RAM, ROM, EPROM, EEPROM, flash memory or other solid state memorytechnology, CD-ROM, DVD, or other optical storage, magnetic cassettes,magnetic tape, magnetic disk storage or other magnetic storage devices,or any other medium that can be used to store the desired informationand that can be accessed by components of the system.

In the embodiment shown, a time processing unit (TPU) 58 may providetiming control signals to light drive circuitry 60, which may controlthe activation of light source 16. For example, TPU 58 may control pulsetiming (e.g., pulse duration and inter-pulse interval) for TD-PAmonitoring system. TPU 58 may also control the gating-in of signals fromdetector 18 through amplifier 62 and switching circuit 64. The receivedsignal from detector 18 may be passed through amplifier 66, low passfilter 68, and analog-to-digital converter 70. The digital data may thenbe stored in a queued serial module (QSM) 72 (or buffer) for laterdownloading to RAM 54 as QSM 72 is filled. In some embodiments, theremay be multiple separate parallel paths having components equivalent toamplifier 66, filter 68, and/or A/D converter 70 for multiple lightwavelengths or spectra received. Any suitable combination of components(e.g., microprocessor 48, RAM 54, analog to digital converter 70, anyother suitable component shown or not shown in FIG. 2) coupled by bus 50or otherwise coupled (e.g., via an external bus), may be referred to as“processing equipment.”

In the embodiment shown, light source 16 may include modulator 44, inorder to, for example, perform FD-PA analysis. Modulator 44 may beconfigured to provide intensity modulation, spatial modulation, anyother suitable optical signal modulations, or any combination thereof.For example, light source 16 may be a CW light source, and modulator 44may provide intensity modulation of the CW light source such as using alinear sweep modulation. In some embodiments, modulator 44 may beincluded in light drive 60, or other suitable components ofphysiological monitoring system 10, or any combination thereof.

In some embodiments, microprocessor 48 may determine the subject'sphysiological parameters, such as SpO₂, SvO₂, oxy-hemoglobinconcentration, deoxy-hemoglobin concentration, total hemoglobinconcentration (tHb), pulse rate, cardiac output, intrathoracic bloodvolume, intrathoracic circulatory volume, global end-diastolic volume,pulmonary circulatory volume, extravascular lung water, and/or otherphysiological parameters, using various algorithms and/or lookup tablesbased on the value of the received signals and/or data corresponding tothe acoustic response received by detector 18. Signals corresponding toinformation about subject 40, and particularly about the acousticsignals emanating from a subject's tissue over time, may be transmittedfrom encoder 42 to decoder 74. These signals may include, for example,encoded information relating to subject characteristics. Decoder 74 maytranslate these signals to enable the microprocessor to determine thethresholds based at least in part on algorithms or lookup tables storedin ROM 52. In some embodiments, user inputs 56 may be used to enterinformation, select one or more options, provide a response, inputsettings, provide any other suitable inputting function, or anycombination thereof. User inputs 56 may be used to enter informationabout the subject such as, for example, age, weight, height, diagnosis,medications, treatments, and so forth. In some embodiments, display 20may exhibit a list of values, which may generally apply to the subject,such as, for example, age ranges or medication families, which the usermay select using user inputs 56.

Calibration device 80, which may be powered by monitor 14 via acommunicative coupling 82, a battery, or by a conventional power sourcesuch as a wall outlet, may include any suitable signal calibrationdevice. Calibration device 80 may be communicatively coupled to monitor14 via communicative coupling 82, and/or may communicate wirelessly (notshown). In some embodiments, calibration device 80 is completelyintegrated within monitor 14. In some embodiments, calibration device 80may include a manual input device (not shown) used by an operator tomanually input reference signal measurements obtained from some othersource (e.g., an external invasive or non-invasive physiologicalmeasurement system).

The acoustic signal attenuated by the tissue of subject 40 can bedegraded by noise, among other sources. Movement of the subject may alsointroduce noise and affect the signal. For example, the contact betweenthe detector and the skin, or the light source and the skin, can betemporarily disrupted when movement causes either to move away from theskin. Another potential source of noise is electromagnetic coupling fromother electronic instruments.

Noise (e.g., from subject movement) can degrade a sensor signal reliedupon by a care provider, without the care provider's awareness. This isespecially true if the monitoring of the subject is remote, the motionis too small to be observed, or the care provider is watching theinstrument or other parts of the subject, and not the sensor site.Processing sensor signals may involve operations that reduce the amountof noise present in the signals, control the amount of noise present inthe signal, or otherwise identify noise components in order to preventthem from affecting measurements of physiological parameters derivedfrom the sensor signals.

FIG. 3 is an illustrative signal processing system 300 in accordancewith an embodiment that may implement the signal processing techniquesdescribed herein. In some embodiments, signal processing system 300 maybe included in a physiological monitoring system (e.g., physiologicalmonitoring system 10 of FIGS. 1-2). In the illustrated embodiment, inputsignal generator 310 generates an input signal 316. As illustrated,input signal generator 310 may include pre-processor 320 coupled tosensor 318, which may provide input signal 316. In some embodiments,pre-processor 320 may be a photoacoustic module and input signal 316 maybe a photoacoustic signal. In an embodiment, pre-processor 320 may beany suitable signal processing device and input signal 316 may includeone or more photoacoustic signals and one or more other physiologicalsignals, such as a photoplethysmograph signal. It will be understoodthat input signal generator 310 may include any suitable signal source,signal generating data, signal generating equipment, or any combinationthereof to produce input signal 316. Input signal 316 may be a singlesignal, or may be multiple signals transmitted over a single pathway ormultiple pathways.

Pre-processor 320 may apply one or more signal processing operations tothe signal generated by sensor 318. For example, pre-processor 320 mayapply a predetermined set of processing operations to the signalprovided by sensor 318 to produce input signal 316 that can beappropriately interpreted by processor 312, such as performing A/Dconversion. In some embodiments, A/D conversion may be performed byprocessor 312. Pre-processor 320 may also perform any of the followingoperations on the signal provided by sensor 318: reshaping the signalfor transmission, multiplexing the signal, modulating the signal ontocarrier signals, compressing the signal, encoding the signal, andfiltering the signal.

In some embodiments, input signal 316 may be coupled to processor 312.Processor 312 may be any suitable software, firmware, hardware, orcombination thereof for processing input signal 316. For example,processor 312 may include one or more hardware processors (e.g.,integrated circuits), one or more software modules, andcomputer-readable media such as memory, firmware, or any combinationthereof. Processor 312 may, for example, be a computer or may be one ormore chips (i.e., integrated circuits) such as, for example, a fieldprogrammable gate array (FPGA), micro-controller, or digital signalprocessor (DSP). Processor 312 may, for example, include an assembly ofanalog electronic components. Processor 312 may calculate physiologicalinformation. For example, processor 312 may perform time domaincalculations, spectral domain calculations, time-spectraltransformations (e.g., fast Fourier transforms, inverse fast Fouriertransforms), any other suitable calculations, or any combinationthereof. Processor 312 may perform any suitable signal processing ofinput signal 316 to filter input signal 316, such as any suitableband-pass filtering, adaptive filtering, closed-loop filtering, anyother suitable filtering, and/or any combination thereof. Processor 312may also receive input signals from additional sources (not shown). Forexample, processor 312 may receive an input signal containinginformation about treatments provided to the subject. Additional inputsignals may be used by processor 312 in any of the calculations oroperations it performs in accordance with processing system 300.

In some embodiments, all or some of pre-processor 320, processor 312, orboth, may be referred to collectively as processing equipment. Forexample, processing equipment may be configured to amplify, filter,sample and digitize input signal 316 (e.g., using an analog to digitalconverter), and calculate physiological information from the digitizedsignal.

Processor 312 may be coupled to one or more memory devices (not shown)or incorporate one or more memory devices such as any suitable volatilememory device (e.g., RAM, registers, etc.), non-volatile memory device(e.g., ROM, EPROM, magnetic storage device, optical storage device,flash memory, etc.), or both. In some embodiments, processor 312 maystore physiological measurements or previously received data from signal316 in a memory device for later retrieval. In some embodiments,processor 312 may store calculated values, such as pulse rate, bloodpressure, blood oxygen saturation (e.g., arterial, venous, or both),hemoglobin concentration (e.g., oxygenated, deoxygenated, and/or total),cardiac output, intrathoracic blood volume, intrathoracic circulatoryvolume, global end-diastolic volume, pulmonary circulatory volume,extravascular lung water, or any other suitable calculated values, orcombinations thereof, in a memory device for later retrieval.

Processor 312 may be coupled to output 314. Output 314 may be anysuitable output device such as one or more medical devices (e.g., amedical monitor that displays various physiological parameters, amedical alarm, or any other suitable medical device that either displaysphysiological parameters or uses the output of processor 312 as aninput), one or more display devices (e.g., monitor, PDA, mobile phone,any other suitable display device, or any combination thereof), one ormore audio devices, one or more memory devices (e.g., hard disk drive,flash memory, RAM, optical disk, any other suitable memory device, orany combination thereof), one or more printing devices, any othersuitable output device, or any combination thereof.

It will be understood that system 300 may be incorporated into system 10(FIGS. 1 and 2) in which, for example, input signal generator 310 may beimplemented as part of sensor unit 12 (FIGS. 1 and 2) and monitor 14(FIGS. 1 and 2) and processor 312 may be implemented as part of monitor14 (FIGS. 1 and 2). In some embodiments, portions of system 300 may beconfigured to be portable. For example, all or part of system 300 may beembedded in a small, compact object carried with or attached to thesubject (e.g., a watch, other piece of jewelry, or a smart phone). Insome embodiments, a wireless transceiver (not shown) may also beincluded in system 300 to enable wireless communication with othercomponents of system 10 (FIGS. 1 and 2). As such, system 10 (FIGS. 1 and2) may be part of a fully portable and continuous physiologicalmonitoring solution. In some embodiments, a wireless transceiver (notshown) may also be included in system 300 to enable wirelesscommunication with other components of system 10. For example,pre-processor 320 may output signal 316 (e.g., which may be apre-processed photoacoustic signal) over BLUETOOTH, IEEE 802.11, WiFi,WiMax, cable, satellite, Infrared, any other suitable transmissionscheme, or any combination thereof. In some embodiments, a wirelesstransmission scheme may be used between any communicating components ofsystem 300.

It will also be understood that while some of the equations referencedherein are continuous functions, the processing equipment may beconfigured to use digital or discrete forms of the equation inprocessing the acquired PA signal.

FIG. 4 shows an illustrative photoacoustic arrangement 400, inaccordance with some embodiments of the present disclosure. Light source402, controlled by a suitable light drive (e.g., a light drive of system300 or system 10, although not shown in FIG. 4), may provide photonicsignal 404 to subject 450. Photonic signal 404 may be attenuated alongits pathlength in subject 450 prior to reaching site 408 of blood vessel452, and may be attenuated across blood vessel 452. It will beunderstood that photonic signal 404 may scatter in subject 450 and neednot travel as a constant, well-formed beam as illustrated. Also,photonic signal 404 may generally travel through and beyond site 408,although not illustrated in FIG. 4. A constituent of the blood in bloodvessel 452 such as, for example, hemoglobin, or an injected indicator(e.g., a dye) may absorb at least some of photonic signal 404 at site408. Accordingly, the blood may exhibit an acoustic pressure responsevia the photoacoustic effect, which may act on the surrounding tissuesof blood vessel 452. Acoustic detector 420 may detect acoustic pressuresignals 410 traveling though tissue of subject 450, and output (notshown) a photoacoustic signal that may be processed by suitableprocessing equipment. Changes in some properties of the blood in bloodvessel 452 at site 408 may be detected by acoustic detector 420. Forexample, a reduced hemoglobin concentration or reduced temperature atthe monitoring site may cause a reduced acoustic pressure signal to bedetected by acoustic detector 420. In some embodiments, bolus dose 460,which may include a suitable indicator, may be introduced to the bloodof patient 450 at a suitable blood vessel site (not shown in FIG. 4).Acoustic detector 420 may detect the transient changes in the hemoglobinconcentration (“hemo-dilution”) and/or temperature (“thermo-dilution”)at site 408 due to passage of bolus dose 460 through site 408. In someembodiments (not shown), multiple monitoring sites may be used to detectchanges in hemoglobin concentration, temperature, or both. As bolus dose460 travels through the circulatory system of subject 450, diffusion,mixing (e.g., within a heart chamber), or both may spread the hemoglobinconcentration and temperature profiles axially (i.e., in the directionof flow) and radially (i.e., normal to the direction of flow). It willbe understood that hemo-dilution refers to the dilution of bloodconstituents caused by the bolus dose, and thermo-dilution refers to thecombined effects of blood constituent dilution and temperature change,both caused by the bolus dose. In some embodiments, by using athermo-dilution indicator, a temperature change may be enhanced byhemo-dilution (e.g., when the temperature change and the dilution changeboth cause the photoacoustic signal to either increase or decrease), andaccordingly may be detected by a system having relatively lesstemperature sensitivity.

Dilution techniques using a bolus dose may be used to determine, forexample, cardiac output (CO), intrathoracic blood volume (ITBV),intrathoracic circulatory volume (ITCV), global end-diastolic volume(GEDV), pulmonary circulatory volume (PCV), extravascular lung water(EVLW), and/or other hemodynamic parameters.

A bolus dose of an indicator may cause the properties at a photoacousticmonitoring site to change in time as the bolus dose passes the site.Introduction of the indicator may alter one or more properties of theblood that interacts with the indicator (e.g., blood near the bolusdose). An indicator introduced as a bolus dose may be selected to haveone or more properties that allow the bolus dose to be distinguishedfrom a subject's un-dosed blood. For example, an indicator may beselected which has particular absorption properties at one or moreparticular wavelengths (e.g., a dye indicator such as indocyanine greendye), and the photoacoustic monitoring system may monitor the presenceof the indicator by providing a photonic signal at the one or moreparticular wavelengths and detecting an acoustic pressure signal havinga dye indicator dilution response. In a further example, an indicatormay be selected to dilute blood of a subject but not substantiallyabsorb the photonic signal. The photoacoustic monitoring system may thenaccordingly monitor the blood (e.g., hemoglobin) rather than theindicator, to detect dilution. In a further example, an indicator havinga temperature different from the temperature of the subject's un-dosedblood may be introduced into a subject's bloodstream (e.g., a “hot” or“cold” indicator, relative to the blood temperature). The photoacousticmonitoring system may then accordingly monitor the bloodstreamtemperature at the monitoring site, or the combined effects ofhemo-dilution and thermo-dilution achieved by the bolus dose. In someembodiments, an indicator may have more than one property that may bedistinguished from a subject's blood. For example, a cold dye indicatormay be introduced to the subject's bloodstream, which may allowhemo-dilution and thermo-dilution effects to be detected. In someembodiments, more than one indicator may be introduced to the subject'sbloodstream, each indicator having particular properties that may beunique relative to the other indicators. For example, an isotonicindicator and a hypertonic indicator may be introduced into a subject'sbloodstream. In a further example, a cold isotonic indicator and a dyeindicator may be introduced into a subject's bloodstream.

FIG. 5 shows an illustrative indicator arrangement 500, in accordancewith some embodiments of the present disclosure. In some embodiments, anindicator may be provided to the circulatory system of a subject to aidin determining one or more physiological parameters. For example, asaline solution may be injected into a subject's circulatory system atblood vessel site 510 using needle 502. Blood vessel site 510 may belocated at any suitable portion of a subject's circulatory system suchas a vein, an artery, a capillary, or other suitable location. Forexample, blood vessel site 510 may be a central vein of the subject.Portion 520 of the subject's circulatory system shown illustratively inFIG. 5 may include heart chambers, arteries, veins, capillaries, anyother suitable parts of the circulatory system, or any combinationthereof. As the indicator travels along portion 520, in the direction ofthe motion arrows, the concentration and/or temperature profile of maychange. For example, panel 550 shows an illustrative dilution curve timeseries as detected at site 552, relatively near site 510. Panels 560 and570 each show illustrative time series of dilution curves at sites 562and 572, respectively, both downstream from site 552. The dilution curveshown in panel 560 is relatively flattened in time compared to thedilution curve shown in panel 550. The dilution curve shown in panel 570is relatively flattened in time compared to the dilution curve shown inpanel 560. The flattening may be due to diffusion and mixing of theindicator with the subject's blood. The area under the time series ofpanels 550, 560, and 570 may be, but need not be, the same and maydepend on the indicator type, travel time, site location, and othersuitable variables. The phrase “dilution curve” as used herein shallrefer to a time series, continuous or discrete, indicative of dilutiveeffects of an indicator on the concentration of blood constituentsand/or blood temperature. For example, a dilution curve may include atime series of concentration or changes thereof of a blood constituent,an indicator, or both. In a further example, a dilution curve mayinclude a time series of temperature, or change in temperature, of bloodof the subject at a monitoring site.

In some embodiments, an indicator may be introduced to a vena cava orother vein. A photoacoustic monitoring system may be used tonon-invasively detect the presence of the indicator in an arterialvessel (e.g., pulmonary artery, brachial artery, carotid artery, aorta)of the subject. The blood travels from the venous system to the rightatrium and then ventricle, from which it is pumped to the lungs via thepulmonary arteries. Transport of water and other substances between thelungs and blood vessels occurs at the lung tissue. Accordingly, lungwater may diffuse to the blood stream, depending upon the chemicalpotential difference of water between the lung tissue and the bloodstream. Oxygenated blood leaving the lung tissue and returning to theheart is pumped by the left atrium and ventricle to the body via theaorta and other suitable portions of the arterial system of the subject.Characteristics of a measured dilution curve may provide an indicationof CO of the subject. The dilatory effects of the indicator in the bloodmay depend on the interaction in the lung tissue, and may provide anindication of parameters such as, for example, EVLW. Properties of thesubject's vasculature may be determined based at least in part on themeasured dilution curves.

Isotonic and Hypertonic Indicators

In some embodiments, more than one indicator may be introduced to thesubject's circulatory system at the same time or in succession. Forexample, in some embodiments, an isotonic indicator (e.g., 0.9% w/vsaline) and a hypertonic indicator (e.g., 5% w/v saline) may beintroduced in succession, and respective dilution curves may be measuredfor both indicators. Shown in FIG. 6 are illustrative dilution curves602 and 652 for isotonic and hypertonic saline indicators, respectively,in accordance with some embodiments of the present disclosure. Theabscissa of each of illustrative plots 600 and 650 are shown in units oftime, while the ordinate of each of illustrative plots 600 and 650 areshown in arbitrary units. In some embodiments, dilution curves such as,for example, dilution curves 602 and 652 may be time series in units ofindicator concentration, tHb, temperature, photoacoustic signal, changein tHb, change in temperature, change in photoacoustic signal, or anyother suitable units indicative of an indicator dilution response.

Plot 600 shows dilution curve 602 indicative of introduction of anisotonic indicator to a subject's bloodstream. Dilution curve 602 isunipolar, and exhibits a peak 604, followed by a gradual steadying to asteady-state value. Because the isotonic indicator includes water havinga chemical potential approximately equal to that of, for example, waterin the lung tissue, the net diffusion of the indicator out of the vesselis zero.

Plot 650 shows dilution curve 652 indicative of introduction of ahypertonic indicator to a subject's bloodstream. Dilution curve 652 isbipolar, and exhibits a peak 654, followed by a trough 656, and then agradual steadying to a steady-state value. Because the hypertonicindicator includes water having a chemical potential less than that of,for example, lung tissue, the net diffusion of the indicator out of thevessel may be nonzero. Water diffuses from the lung tissue to the blood,due to the imbalanced chemical potential of water across the permeablelung/vessel interfaces. This interaction may reduce the chemicalpotential of water in the lung tissue. Peak 654 indicates the increaseddilution due to the indicator and the water transferred from the lung inthe bloodstream. Accordingly, as the bolus dose of indicator travelsaway from the lung tissue via the pulmonary vein, blood with reducedindicator content, upstream of the bolus dose, reaches the lung tissue.The chemical potential imbalance then reverses, and water diffuses tothe lung tissue from the blood. Trough 656 indicates the decreaseddilution due to the transport of water from the bloodstream to the lungtissue. In some circumstances, the effect of the indicator may bereduced as time progresses, due to mixing and/or bio-regulation,illustratively indicated by the gradual return of dilution curves 602and 652 to a steady-state, or near steady-state, condition.

FIG. 7 shows a plot 700 of an illustrative time domain photoacousticsignal 702, including a response corresponding to an isotonic indicator,in accordance with some embodiments of the present disclosure.Photoacoustic signal 702 may be a pre-processed and/or processed signalderived from the output of an acoustic detector. For example,photoacoustic signal 702 may include sample points corresponding to amaximum acoustic response for each light pulse (e.g., an acousticpressure peak value), at a particular time lag corresponding to aparticular spatial location (e.g., a particular blood vessel). Theabscissa of plot 700 is shown in units of time, while the ordinate ofplot 700 is shown in units proportional to voltage. A light source isused to provide a photonic signal to a first site of a circulatorysystem, causing a photoacoustic response of constituents in thecirculating blood at that site. An acoustic detector is used to detectacoustic pressure signals caused by the photonic signal at the firstsite, and output photoacoustic signal 702. An isotonic indicator isinjected as a bolus dose into the circulating blood at a second site. Asthe bolus dose travels past the first site, the hemoglobin concentrationat the first site temporarily decreases. Trough 704 indicates thedilatory effects of the bolus dose of isotonic indicator. The acousticdetector detects a reduced acoustic pressure signal caused by thereduced hemoglobin concentration. The effect of the indicator may bedetected as a trough in the acoustic pressure signal corresponding tothe passing of the bolus dose through the first site. Note thatphotoacoustic signal 702 may be indicative of tHb, exhibiting asubstantially steady-state baseline and trough 704 indicative of thepresence of the indicator (e.g., a reduction of tHb via displacement bythe indicator). Note that a plot of indicator concentration as afunction of time may exhibit a peak, corresponding to a steady-state tHbvalue minus an instantaneous tHb value. A dilution curve may includeeither a peak or a trough depending upon the species monitored and theunits used in calculation.

FIG. 8 shows an illustrative plot 800 of two total hemoglobinconcentration time series as respective isotonic and hypertonicindicators pass a photoacoustic detection site, in accordance with someembodiments of the present disclosure. The abscissa of plot 800 is shownin units of time, and the ordinate of plot 800 is shown in units oftotal hemoglobin concentration, although any suitable units may be usedin accordance with the present disclosure. Time series 802 and 804 maybe pre-processed and/or processed signals derived from the output of anacoustic detector. For example, time series 802 and 804 may each includesample points corresponding to a maximum acoustic response for eachlight pulse (e.g., an acoustic pressure peak value), at a particulartime lag corresponding to a particular spatial location (e.g., aparticular blood vessel). Time series 802 is total hemoglobinconcentration as the isotonic indicator travels through thephotoacoustic detection site. Alternatively, if the indicatorconcentration were shown rather than tHb, it may exhibit a peak ratherthan a trough, corresponding to the shaded area 820. Time series 804 istotal hemoglobin concentration as the hypertonic indicator travelsthrough the photoacoustic detection site. The variable t as shown inFIG. 8 represents time relative to each response, and not an absolutetime scale. For example, the time origin for both responses may be zero,and they may be plotted on the same axis even though the indicators wereintroduced at different times. The variable τ as shown in FIG. 8represents the mean transit time difference between the two responses.

In some embodiments, one or more characteristics may be derived from oneor both responses. For example, the flow rate of a particular indicatormay be formulated as shown by:{dot over (V)}C _(i) ={dot over (N)}  (14)where {dot over (V)} is the volumetric flow rate of blood (e.g.,volume/time, assumed here to be constant in time), C_(i) is theconcentration of indicator i (e.g., mole/volume, equivalent to thereduction in tHb using suitable assumptions), and {dot over (N)} is themolar flow rate of molecule i (e.g., mole/time). Defining the cardiacoutput CO to be equal to volumetric flow rate {dot over (V)}, andreferencing time series 802, the following Eq. 15 may be derived byintegrating both sides of Eq. 14 in time:

$\begin{matrix}{{C\; O} = \frac{N}{A}} & (15)\end{matrix}$where cardiac output CO is proportional to the total isotonic indicatoramount introduced N (e.g., moles, equivalent to the time integral of{dot over (N)}), and A is given by:A=∫C _(i) dt  (16)where A may be equivalent to the area 820 bounded by time series 802 andthe steady tHb value. If the ordinate of plot 800 were shown in unitsother than concentration, a constant of proportionality may be requiredin Eq. 16 if time series values are used. Under some circumstances,cardiac output may be equal to the ratio of isotonic indicator amountintroduced and the area bounded by the time series and the steady tHbvalue, while in other circumstances the equality of Eqs. 15-16 may bereplaced by the proportionality symbol ∝ (e.g., to account for densitydifferences). Area A is an illustrative example of a characteristicderived from a response to an indicator.

In a further example, EVLW may be formulated based on both time series802 and 804, as shown by Eq. 17:EVLW=CO*Δτ_(MT)  (17)where CO is the cardiac output, and Δτ_(MT) is the mean transit timedifference between the isotonic and hypertonic indicator dilutioncurves. The mean transit time of an indicator dilution curve may bebased on any suitable reference point of the curve. The mean transittime for a dilution curve may be calculated using Eq. 18:

$\begin{matrix}{\tau_{MT} = {\tau_{0} + \frac{\int{C_{i}*\left( {t - \tau_{0}} \right){\mathbb{d}t}}}{\int{C_{i}{\mathbb{d}t}}}}} & (18)\end{matrix}$where τ₀ is the time after introduction of the indicator when theindicator is detected at the PA monitoring site, and C_(i) is theindicator concentration.

In a further example, a vascular permeability metric vp may be definedas:vp=τ ₂−τ₁  (19)where τ₂ is the peak time of time series 804, and τ₁ is the time wheretime series 802 and 804 cross. In some circumstances, vascularpermeability may provide an indication and/or measure of the possibilityof a capillary leak and the possibility of fluid accumulating outside ofthe blood vessels.

In a further example, EVLW may be determined based on an osmoticresponse (e.g., the transfer of water and salt between the blood andlungs due to a chemical potential difference) of the subject using anisotonic and hypertonic indicator. EVLW may be determined using thefollowing Eq. 20, for the hypertonic indicator:

$\begin{matrix}{{E\; V\; L\; W} = \frac{\Pi_{b}\left( {\frac{\Delta\; n_{3}}{c} - {\Delta\; E\; V\; L\; W_{3}}} \right)}{{\Delta\Pi}_{b,3}}} & (20)\end{matrix}$where Π_(b) is the steady state osmolarity of the subject's blood (e.g.,before introduction of the hypertonic indicator), ΔΠ_(b,3) is the changein the osmolarity of subject's blood at time τ₃, Δn₃ is the total amountof salt transferred from the subject's blood to the subject's lungs attime τ₃, c is the concentration of solutes in the EVLW, and ΔEVLW₃ isthe total change in extravascular lung water at time τ₃. The time τ₃ isthe time, referenced to zero at the beginning of the response, when theEVLW and blood have the same osmotic pressure for the hypertonicindicator.

Thermo-Dilution Indicators

In some embodiments, a thermo-dilution indicator may be introduced tothe subject's circulatory system at a suitable location. For example, insome embodiments, a saline solution having a temperature less than thatof a subject's blood may be introduced, and one or more dilution curvesmay be measured at one or more respective locations in the subject'svasculature. The Grüneisen parameter of the subject's blood may dependon temperature linearly according to the illustrative empiricalrelation:Γ=mT+b  (21)where m is a slope and b is an intercept. Accordingly, Eq.1 may be rewritten as follows:p(z,T)=Γ(T)μ_(a)φ(z).  (22)Showing that as the temperature at the photoacoustic monitoring sitechanges, the acoustic pressure signal may change accordingly.Introduction of thermo-dilution indicator may be used to determinecardiac output, ITCV, PCV, and/or GEDV, for example.

In some embodiments, cardiac output CO may be calculated using:

$\begin{matrix}{{C\; O} = {K\frac{\left( {T_{b,0} - T_{i,0}} \right)V_{i}}{\int{\left( {T_{b,0} - {T_{b}(t)}} \right){\mathbb{d}t}}}}} & (23)\end{matrix}$where K is a proportionality constant (e.g., including the effects ofspecific gravity and heat capacity of blood and/or the indicator),T_(b,0) is the initial blood temperature at the time and site ofinjection, T_(i,0) is the initial indicator temperature, V_(i) is thevolume of injected indicator, and T_(b)(t) is the blood temperature attime t, as measured using the photoacoustic technique. Note that themoles of injected indicator may be used rather than V_(i) in some cases,with a suitable adjustment of the proportionality constant K to includethe indicator concentration (e.g., mole/volume). In some embodiments, anexpression such as, for example, Eq. 22 may be solved for temperature asa function of photoacoustic signal, and the function may include one ormore parameters that may depend on tissue properties and/or systemproperties. Accordingly, a photoacoustic monitoring system (e.g., system10 of FIGS. 1-2 or system 300 of FIG. 3) may use one or more referencessuch as pre-defined constants, reference PA signals, correlations, orlook-up tables to determine a temperature, or change thereof, from adetected acoustic pressure signal. In some embodiments, a photoacousticmonitoring system may be calibrated for a particular subject orparticular monitoring site of a subject. In some embodiments, aphotoacoustic monitoring system may use a thermo-dilution indicatorresponse and a body-temperature hemo-dilution indicator response (e.g.,to de-couple the temperature and concentration effects) to determine atemperature or change thereof.

In some embodiments, ITCV may be calculated using:ITCV=CO*τ_(MT)  (24)where CO is cardiac output (e.g., which may be calculated using Eq. 23),and τ_(MT) is the mean transit time of the thermo-dilution curve. Themean transit time for a thermo-dilution indicator may be calculatedusing:

$\begin{matrix}{\tau_{MT} = {\tau_{0} + \frac{\int{\left( {T_{b,0} - {T_{b}(t)}} \right)*\left( {t - \tau_{0}} \right){\mathbb{d}t}}}{\int{\left( {T_{b,0} - {T_{b}(t)}} \right){\mathbb{d}t}}}}} & (25)\end{matrix}$where τ₀ is the time after introduction of the indicator when theindicator is detected at the PA monitoring site, and (T_(b,0)−T_(b)(t))is the difference in initial and instantaneous blood temperature of thethermo-dilution curve. In some embodiments, in which a thermo-dilutionindicator may be used, a circulatory volume may be equivalent to athermal volume.

In some embodiments, PCV may be calculated using:PCV=CO*τ_(DS)  (26)where CO is the cardiac output, and τ_(DS) is the downslope time of thethermo-dilution curve. In some embodiments, the downslope time may bedetermined as the time interval of the linear decay of the indicatorresponse (e.g., downslope of a peak), from about 80% of the peak valueto about 20% of the peak value. In some circumstances, downslope timemay provide an indication and/or measure of the washout of theindicator, which may depend on the volume which the indictor dilutes.

In some embodiments, GEDV may be calculated using:GEDV=ITCV−PCV  (27)which may be indicative of the blood volume included in the ITCV.

In some embodiments, EVLW may be calculated using:EVLW=ITCV−ITBV  (28)where ITBV may be calculated from GEDV, which may be calculated usingEq. 27. For example, ITBV may be directly proportional to GEDV, with aproportionality constant of order one (e.g., a constant of 1.25).Accordingly, in some embodiments, ITCV, PCV, GEDV, ITBV, and EVLW may bedetermined based on a thermo-dilution indicator.

Hemo-Dilution and Thermo-Dilution Indicators

In some embodiments, both a thermo-dilution indicator and ahemo-dilution indicator may be introduced to the subject's circulatorysystem at suitable locations and times. For example, in someembodiments, a saline solution having a temperature less than that of asubject's blood may be introduced, and a dye indicator such asindocyanine green dye may be introduced. Accordingly, two or moredilution curves may be measured at one or more locations in thesubject's vasculature, indicative of the hemo-dilution andthermo-dilution indicators. Any of the properties that may be calculatedusing Eqs. 21-27 may be calculated using the thermo-dilution indicator.In some embodiments, ITBV may be calculated using the hemo-dilutioncurve, as shown by:ITBV=CO*τ_(MT)  (29)where CO is the cardiac output (e.g., calculated using Eq. 15 or 23),and τ_(MT) is the mean transit time of the hemo-dilution curve (e.g.,calculated using Eq. 18).

In some embodiments, EVLW may be calculated from the thermo-dilutioncurve and hemo-dilution curve using:EVLW=ITCV−ITBV  (30)wherein ITCV may be calculated from the thermo-dilution curve (e.g.,using Eq. 24), and ITBV may be calculated from the hemo-dilution curve(e.g., using Eq. 29).

Any of the thermal-dilution and hemo-dilution techniques, using one ormore indicators, including the use of an isotonic and a hypertonicindicator, may be used alone or in combination with other techniques.Accordingly, any of Eqs. 14-30 may be used alone or in concert todetermine physiological information of a subject such as a physiologicalparameter. FIGS. 9-12 include flowcharts of illustrative steps forimplementing the aforementioned techniques. In some embodiments, otherinformation may be determined based on indicator dilution techniques(e.g., using an indocyanine green indicator, liver function and/or totalblood volume may be determined).

FIG. 9 is a flow diagram 900 of illustrative steps for determining aphysiological parameter from an acoustic pressure signal having anindicator dilution response, in accordance with some embodiments of thepresent disclosure.

Step 902 may include a suitable light source (e.g., light source 16 ofsystem 10) of system 300 providing a photonic signal to a subject. Thelight source may be a pulsed light source, continuous wave light source,any other suitable light source, or any combination thereof. In someembodiments, modulator 44 may be used to modulate the photonic signal ofthe light source. In some embodiments, the photonic signal may befocused or otherwise spatially modulated. For example, the photonicsignal may be focused on or near a blood vessel, which may contain bloodthat absorbs at least some of the photonic signal, causing a relativelystronger photoacoustic response and accordingly a stronger photoacousticsignal than surrounding tissue.

Step 904 may include system 300 detecting an acoustic pressure signalhaving an indicator response. In some embodiments, an acoustic detectorsuch as, for example, an ultrasound detector of system 300 may detectthe acoustic pressure signal. The acoustic detector may output anelectrical signal to suitable processing equipment of system 300. Theacoustic pressure signal may be detected as a time series (e.g., in thetime domain or sample number domain), and processed as a time series, asa spectral series (e.g., in the frequency domain), any other suitableseries, or any combination thereof. In some embodiments, pre-processor320 may pre-process the detected acoustic pressure signal. For example,pre-processor 320 may perform filtering, amplifying, de-multiplexing,de-modulating, sampling, smoothing, any other suitable pre-processing,or any combination thereof. The acoustic pressure signal may include ahemo-dilution and/or thermo-dilution response characterized by atemporal peak or trough in concentration, temperature, any othersuitable property of the monitoring site, any changes thereof, or anycombination thereof. In some embodiments, processor 312 may use a peakfinding technique to locate a peak and/or trough. For example, processor312 may locate a maximum or minimum in the photoacoustic signal, locatea zero in the first derivative of the photoacoustic signal, perform anyother suitable peak finding technique, or any combination thereof. Thepeak finding technique may operate on only a subset of the photoacousticsignal. For example, the peak finding algorithm may only start lookingfor a peak and/or trough after a predetermined time or sample numberfrom the introduction of the indicator. In some embodiments, processor312 and/or pre-processor 320 may generate a photoacoustic signal from atime series of peak values in a detected acoustic pressure signal,occurring at a particular time lag indicative of a spatial location,resulting from the photoacoustic response to the photonic signal.

Step 906 may include system 300 determining one or more physiologicalparameters of the subject based at least in part on the indicatordilution response detected at step 904. Physiological parameters mayinclude hemoglobin, blood oxygen saturation, CO, ITBV, ITCV, GEDV, PCV,EVLW, any other suitable hemodynamic parameters, any other suitablephysiological parameters, any physiological modulations thereof, or anycombination thereof. In some embodiments, step 906 may include processor312 determining one or more characteristics based at least in part onthe indicator dilution response. Processor 312 may determinecharacteristics such as particular values of the acoustic pressuresignal or values of a signal derived thereof (e.g., a tHb value), areasunder or between signals (e.g., integrals), temporal values ordifferences (e.g., as shown by Eqs. 18, 19, and 25), any other suitablecharacteristics, or any combination thereof. For example, processor 312may calculate one or more physiological parameters using any or all ofEqs. 14-16, 18, and 23-29, based on a detected indicator dilutionresponse. In some embodiments, an acoustic pressure signal may beinfluenced by arterial pulsations and/or respiratory synchronousvariations, or other biological modulations. In some such embodiments,system 300 may use a spectral filter (e.g., a notch filter, a high-passfilter) to reduce the influence of these biological modulations thattypically occur over larger time scales than the time scales of anacoustic pressure signal. For example, system 300 may apply a spectralfilter to a photoacoustic signal derived from an acoustic pressuresignal, to filter out pulsatile components.

FIG. 10 is a flow diagram 1000 of illustrative steps for determining aphysiological parameter from an acoustic pressure signal having a firstand a second response, in accordance with some embodiments of thepresent disclosure.

Step 1002 may include a suitable light source (e.g., light source 16 ofsystem 10) of system 300 providing a photonic signal to a subject, at amonitoring site. The light source may be a pulsed light source,continuous wave light source, any other suitable light source, or anycombination thereof. In some embodiments, modulator 44 may be used tomodulate the photonic signal of the light source. In some embodiments,the photonic signal may be focused or otherwise spatially modulated. Forexample, the photonic signal may be focused on or near a blood vessel,which may contain blood that absorbs at least some of the photonicsignal, causing a relatively stronger photoacoustic response andaccordingly a stronger photoacoustic signal than surrounding tissue. Insome embodiments, step 1002 may include providing the photonic signal attwo particular times to monitor the respective first and secondresponses. For example, the photonic signal of step 1002 may be providedin response to the introduction of an indicator, at a suitable time tomonitor the response at the monitoring site of the subject. In someembodiments, step 1002 may include providing the photonic signalsteadily, and using processor equipment to locate the response in thetime series.

Step 1004 may include system 300 detecting an acoustic pressure signalhaving a first and a second response. In some embodiments, an acousticdetector such as, for example, an ultrasound detector of system 300 maydetect the acoustic pressure signal. The acoustic detector may output anelectrical signal to suitable processing equipment of system 300. Theacoustic pressure signal may be detected as a time series (e.g., in thetime domain or sample number domain), and processed as a time series, asa spectral series (e.g., in the frequency domain), any other suitableseries, or any combination thereof. In some embodiments, pre-processor320 may pre-process the detected acoustic pressure signal. For example,pre-processor 320 may perform filtering, amplifying, de-multiplexing,de-modulating, sampling, smoothing, any other suitable pre-processing,or any combination thereof. In some embodiments, processor 312 and/orpre-processor 320 may generate a photoacoustic signal from a time seriesof peak values in a detected acoustic pressure signal, occurring at aparticular time lag indicative of a spatial location, resulting from thephotoacoustic response to the photonic signal. The photoacoustic signalmay include a first and a second response, which may be hemo-dilutionand/or thermo-dilution responses. The responses may be characterized bya temporal peak or trough in the photoacoustic signal, a concentrationtime series derived thereof, a temperature time series derived thereof,any other suitable signal, any changes thereof, or any combinationthereof. In some embodiments, processor 312 may use a peak findingtechnique to locate a peak and/or trough. For example, processor 312 maylocate a maximum or minimum in the photoacoustic signal, locate a zeroin the first derivative of the photoacoustic signal, perform any othersuitable peak finding technique, or any combination thereof. The peakfinding technique may operate on only a subset of the photoacousticsignal. For example, the peak finding algorithm may only start lookingfor a peak and/or trough after a predetermined time or sample numberfrom the introduction of the respective indicator.

Step 1006 may include system 300 determining one or more physiologicalparameters of the subject based at least in part on the first and/orsecond responses detected at step 1004. Physiological parameters mayinclude hemoglobin, blood oxygen saturation, CO, ITBV, ITCV, GEDV, PCV,EVLW, any other suitable hemodynamic parameters, any other suitablephysiological parameters, any physiological modulations thereof, or anycombination thereof. In some embodiments, step 1004 may includeprocessor 312 determining one or more characteristics based at least inpart on the first and/or second responses. Processor 312 may determinecharacteristics such as particular values of the acoustic pressuresignal or values of a signal derived thereof (e.g., a tHb value), areasunder or between signals (e.g., integrals), temporal values ordifferences (e.g., as shown by Eqs. 18, 19, and 25), any other suitablecharacteristics, or any combination thereof. For example, processor 312may calculate one or more physiological parameters using any or all ofEqs. 14-20, and 23-30, based on detected first and/or second responses.More particularly, processor 312 may calculate EVLW from an isotonicindicator dilution response and a hypertonic indicator dilution responseusing Eq. 17. Also more particularly, processor 312 may calculate ITBV,ITCV, and EVLW from a hemo-dilution response and a thermo-dilutionresponse using Eqs. 29-30.

FIG. 11 is a flow diagram 1100 of illustrative steps for determining aphysiological parameter from an acoustic pressure signal having a firstand second response, corresponding to respective isotonic and hypertonicindicators, in accordance with some embodiments of the presentdisclosure.

Step 1102 may include a suitable light source (e.g., light source 16 ofsystem 10) of system 300 providing a photonic signal to a subject, at afirst site. The light source may be a pulsed light source, continuouswave light source, any other suitable light source, or any combinationthereof. In some embodiments, modulator 44 may be used to modulate thephotonic signal of the light source. In some embodiments, the photonicsignal may be focused or otherwise spatially modulated.

Step 1104 may include providing an isotonic indicator to a subject at asecond site, at a first time. In some embodiments, a bolus dose of theisotonic indicator may be injected using a hypodermic needle, insertedinto a blood vessel of the subject. The bolus dose may include, forexample, a volume on the order of ten milliliters. Such a dose appliedto the central vein may dilute the blood inside the heart up to tenpercent. In some embodiments, the bolus dose of isotonic indicator maybe introduced at substantially the same temperature of the subject atthe second site. In some embodiments, the bolus dose of isotonicindicator may be introduced at a temperature different from thetemperature of the subject at the second site (e.g., the bolus dose maybe relatively warmer or cooler).

Step 1106 may include providing a hypertonic indicator to a subject ator near the second site, at a second time. In some embodiments, a bolusdose of the hypertonic indicator may be injected using a hypodermicneedle, inserted into a blood vessel of the subject. The bolus dose mayinclude, for example, a volume on the order of ten milliliters. Thesecond time may be before or after the first time (i.e., theintroduction of the isotonic and hypertonic indicators may be in anysuitable order). In some embodiments, the bolus dose of hypertonicindicator may be introduced at substantially the same temperature of thesubject at the second site. In some embodiments, the bolus dose ofhypertonic indicator may be introduced at a temperature different fromthe temperature of the subject at the second site (e.g., the bolus dosemay be relatively warmer or cooler). The bolus dose of hypertonicindicator may be introduced at a temperature the same as, or differentfrom, the temperature of the bolus dose of isotonic indicator of step1104.

Step 1108 may include system 300 detecting an acoustic pressure signalhaving a first and a second response, corresponding to the isotonic andhypertonic indicators. In some embodiments, an acoustic detector suchas, for example, an ultrasound detector of system 300 may detect theacoustic pressure signal. In some embodiments, processor 312 and/orpre-processor 320 may generate a photoacoustic signal from a time seriesof peak values in a detected acoustic pressure signal, occurring at aparticular time lag indicative of a spatial location, resulting from thephotoacoustic response to the photonic signal. The acoustic detector mayoutput an electrical signal to suitable processing equipment of system300. In some embodiments, the first and second responses may be detectedas peaks or troughs in the photoacoustic signal, distinguishable from abaseline photoacoustic signal.

Step 1110 may include system 300 determining one or more characteristicsbased at least in part on the first and/or second response. Processor312 may determine characteristics such as particular values of theacoustic pressure signal or values of a signal derived thereof, areasunder or between dilution curves, temporal values or differences, anyother suitable characteristics, or any combination thereof. For example,a mean transit time may be determined using any of Eqs. 18 or 25. In afurther example, a mean transit time difference may be determined usingEq. 18. In a further example, an integral may be determined using Eq.16. In a further example, a crossing time may be determined such asvariable τ₁ used in Eq. 19. In a further example, a time associated witha peak value may be determined such as variable τ₂ used in Eq. 19. In afurther example, a time difference may be determined using Eq. 19.

Step 1112 may include system 300 determining one or more physiologicalparameters of the subject based at least in part on the one or morecharacteristics of step 1110. Physiological parameters may includehemoglobin, blood oxygen saturation, CO, ITBV, ITCV, GEDV, PCV, EVLW,any other suitable hemodynamic parameters, any other suitablephysiological parameters, any physiological modulations thereof, or anycombination thereof. For example, processor 312 may calculate one ormore physiological parameters based on suitable characteristics usingany or all of Eqs. 14-20.

FIG. 12 is a flow diagram 1200 of illustrative steps for determining aphysiological parameter from an acoustic pressure signal having ahemo-dilution and/or thermo-dilution response, in accordance with someembodiments of the present disclosure.

Step 1202 may include a suitable light source (e.g., light source 16 ofsystem 10) of system 300 providing a photonic signal to a subject, at amonitoring site. The light source may be a pulsed light source,continuous wave light source, any other suitable light source, or anycombination thereof. In some embodiments, modulator 44 may be used tomodulate the photonic signal of the light source. In some embodiments,the photonic signal may be focused or otherwise spatially modulated.

Step 1204 may include determining which indicators are to be introducedto the subject. One or more thermo-dilution indicators, one or morehemo-dilution indicators, or combinations thereof, may be introduced tothe subject. In some embodiments, system 300 may determine whichindicators to introduce to the subject. For example, in order todetermine a particular physiological parameter, system 300 may determinethat particular indicator(s) are required. In some embodiments, step1204 may be performed by a user, who may input one or more commands(e.g., selections from a pull-down menu, entry of a text indication)into a suitable user interface (e.g., user inputs 56 of system 10). Insome embodiments, system 300 may be configured to detect a particularresponse (e.g., thermo-dilution or hemo-dilution), and accordingly step1204 need not be performed because no determination is required.

Step 1206 may include providing one or more thermo-dilution indicatorsto the subject at an indicator site, and then system 300 detecting aresulting thermo-dilution response of an acoustic pressure signal atstep 1208 based at least in part on the photonic signal of step 1202. Insome embodiments, a bolus dose of the thermo-dilution indicator may beinjected using a hypodermic needle, inserted into a blood vessel of thesubject. The bolus dose may include, for example, a volume on the orderof ten milliliters. In some embodiments, the bolus dose ofthermo-dilution indicator may be introduced at a temperature differentfrom the temperature of the subject at the indicator site (e.g., thebolus dose may be relatively warmer or cooler). The thermo-dilutionindicator may be an isotonic indicator, a hypertonic indicator, ahypertonic indicator, a dye indicator, any other suitable indicator, orany combination thereof. In some embodiments, an acoustic detector suchas, for example, an ultrasound detector of system 300 may detect theacoustic pressure signal at step 1208. The acoustic detector may outputan electrical signal to suitable processing equipment of system 300. Insome embodiments, processor 312 and/or pre-processor 320 may generate aphotoacoustic signal from a time series of peak values in a detectedacoustic pressure signal, occurring at a particular time lag indicativeof a spatial location, resulting from the photoacoustic response to thephotonic signal. In some embodiments, the thermo-dilution response maybe detected as a peak or trough in the photoacoustic signal,distinguishable from a baseline photoacoustic signal.

Step 1210 may include providing one or more hemo-dilution indicators tothe subject, and then system 300 detecting a resulting hemo-dilutionresponse of an acoustic pressure signal at step 1212 based at least inpart on the photonic signal of step 1202. In some embodiments, a bolusdose of the hemo-dilution indicator may be injected using a hypodermicneedle, inserted into a blood vessel of the subject. The bolus dose mayinclude, for example, a volume on the order of ten milliliters. Thebolus dose of hemo-dilution indicator may be, but need not be,introduced at the same temperature as the temperature of the subject atthe indicator site. The hemo-dilution indicator may be an isotonicindicator, a hypertonic indicator, a hypertonic indicator, a dyeindicator, any other suitable indicator, or any combination thereof. Insome embodiments, an acoustic detector such as, for example, anultrasound detector of system 300 may detect the acoustic pressuresignal at step 1212. The acoustic detector may output an electricalsignal to suitable processing equipment of system 300. In someembodiments, processor 312 and/or pre-processor 320 may generate aphotoacoustic signal from a time series of peak values in a detectedacoustic pressure signal, occurring at a particular time lag indicativeof a spatial location, resulting from the photoacoustic response to thephotonic signal. In some embodiments, the hemo-dilution response may bedetected as a peak or trough in the photoacoustic signal,distinguishable from a baseline photoacoustic signal.

Step 1214 may include system 300 detecting a thermo-dilution responseand a hemo-dilution response of an acoustic pressure signal based atleast in part on the photonic signal of step 1202, resulting fromrespective thermo-dilution and hemo-dilution indicators provided atsteps 1206 and 1210. In some embodiments, bolus doses of thethermo-dilution and hemo-dilution indicators may be injected using oneor more hypodermic needles, inserted into one or more blood vessels (orsites thereof) of the subject. Each bolus dose may include, for example,a volume on the order of ten milliliters. In some embodiments, anacoustic detector such as, for example, an ultrasound detector of system300 may detect the acoustic pressure signal at step 1208. The acousticdetector may output an electrical signal to suitable processingequipment of system 300. In some embodiments, processor 312 and/orpre-processor 320 may generate a photoacoustic signal from a time seriesof peak values in a detected acoustic pressure signal, occurring at aparticular time lag indicative of a spatial location, resulting from thephotoacoustic response to the photonic signal. In some embodiments, thethermo-dilution and hemo-dilution responses may be detected as peaks ortroughs in the photoacoustic signal, distinguishable from a baselinephotoacoustic signal. In some embodiments, the thermo-dilution indicatorand hemo-dilution indicator may be introduced to the subject atdifferent times and/or locations. For example, a particular timeinterval between the thermo-dilution and hemo-dilution indicators may beused to prevent mixing of the indicators and corresponding compositeeffects.

Step 1216 may include system 300 determining one or more characteristicsbased at least in part on the detected responses of any of steps 1208,1212, and 1214. In some embodiments, the one or more characteristics maydepend on the type of indicator that is provided (e.g., at steps 1206and/or 1210). Characteristics may include particular values of theacoustic pressure signal or values of a signal derived thereof (e.g., aphotoacoustic signal), areas under or between dilution curves, temporalvalues or differences, any other suitable characteristics, or anycombination thereof. For example, one or more thermo-dilution indicatorsmay be used, and the one or more characteristics may include a meantransit time (e.g., as included in Eqs. 24 and 25), a downslope time(e.g., as included in Eq. 26), and an integral of a portion of adilution curve (e.g., as included in Eq. 23). In a further example, oneor more hemo-dilution indicator may be used, and the one or morecharacteristics may include a mean transit time (e.g., as included inEqs. 18 and 29), a time difference (e.g., as included in Eqs. 17 and19), and an integral of a portion of a dilution curve (e.g., as includedin Eq. 16). In a further example, a thermo-dilution indicator and ahemo-dilution indicator may be used, and the one or more characteristicsmay include a mean transit time (e.g., as included in Eqs. 18, 24, 25and 29), a downslope time (e.g., as included in Eq. 26), a timedifference (e.g., as included in Eqs. 17, 19 and 23), and an integral ofa portion of a dilution curve (e.g., as included in Eq. 23).

Step 1218 may include system 300 determining one or more physiologicalparameters of the subject based at least in part on the one or morecharacteristics of step 1216. Physiological parameters may includehemoglobin, blood oxygen saturation, CO, ITBV, ITCV, GEDV, PCV, EVLW,any other suitable hemodynamic parameters, any other suitablephysiological parameters, any physiological modulations thereof, or anycombination thereof. For example, processor 312 may calculate one ormore physiological parameters based on suitable characteristics usingany or all of Eqs. 14-20 and 23-30.

In the foregoing flowcharts, an acoustic pressure signal having one ormore indicators is detected. In some embodiments, the system (e.g.,system 300) may continuously detect the acoustic pressure signal andcontinuously analyze the photoacoustic signal to identify the one ormore indicator responses. In some embodiments, the system may onlydetect and analyze the acoustic pressure signal in response to a userinput. For example, the user may press a key on the monitor shortlybefore the one or more indicators are injected. In some embodiments, thesystem may be communicatively coupled to the injection apparatus andtherefore may automatically know when the one or more indicators areinjected and when to detect the acoustic pressure signal. For example,the injection apparatus may transmit a signal to the system each timethere is an injection. As another example, the system may control theinjection apparatus and instruct the injection apparatus when to performan injection.

The foregoing is merely illustrative of the principles of thisdisclosure and various modifications may be made by those skilled in theart without departing from the scope of this disclosure. The abovedescribed embodiments are presented for purposes of illustration and notof limitation. The present disclosure also can take many forms otherthan those explicitly described herein. Accordingly, it is emphasizedthat this disclosure is not limited to the explicitly disclosed methods,systems, and apparatuses, but is intended to include variations to andmodifications thereof, which are within the spirit of the followingclaims.

What is claimed is:
 1. A method for determining a physiologicalparameter of a subject, the method comprising: providing a photonicsignal to a first blood vessel site of the subject; detecting anacoustic pressure signal from the first blood vessel site using one ormore acoustic detectors, wherein the acoustic pressure signal is causedby the absorption of at least some of the photonic signal by one or moreconstituents at the first blood vessel site, and wherein the acousticpressure signal comprises a thermo-dilution response corresponding to anindicator provided to a second blood vessel site, wherein the indicatoris provided at a temperature different than the temperature of thesecond blood vessel site; and determining cardiac output of the subjectbased on an initial indicator temperature, an initial blood temperatureat a first time, and an adjusted blood temperature at a second time asindicated by the thermo-dilution response and based on an equationhaving the form:${{CO} = \frac{{K\left( {T_{b,0} - T_{i,0}} \right)}V_{i}}{\int{\left( {T_{b,0} - T_{b{(t)}}} \right){\mathbb{d}t}}}},$wherein K is a proportionality constant related to the effects ofspecific gravity and heat capacity of blood, the indicator, or both,T_(b,0) is the initial blood temperature, T_(i,0) is the initialindicator temperature, T_(b(t)) is the adjusted blood temperature, and Vis a volume of the indicator provided to the second blood vessel site.2. The method of claim 1, comprising determining one or more ofintrathoracic blood volume, intrathoracic circulatory volume, globalend-diastolic volume, pulmonary circulatory volume, and extravascularlung water based on the cardiac output and one or more features of athermo-dilution curve that is representative of the thermo-dilutionresponse.
 3. The method of claim 2, wherein the features comprise a meantransit time of the thermo-dilution curve or a downslope time of thethermo-dilution curve.
 4. The method of claim 1, wherein the acousticpressure signal comprises a hemo-dilution response and thethermo-dilution response.
 5. The method of claim 1, wherein the firstblood vessel site is located at an artery of the subject.
 6. The methodof claim 1, wherein the second blood vessel site is located at a vein ofthe subject.
 7. The method of claim 1, wherein the indicator is at leastone of a dye indicator and a saline solution.
 8. The method of claim 1,comprising determining cardiac output based only on: the proportionalityconstant related to the effects of specific gravity and heat capacity ofblood, the indicator, or both; the initial blood temperature; theinitial indicator temperature; the adjusted blood temperature; and thevolume of the indicator provided to the second blood vessel site.
 9. Asystem for determining a physiological parameter of a subject, thesystem comprising: a light source configured to provide a photonicsignal to a first blood vessel site of the subject; an acoustic detectorconfigured to detect an acoustic pressure signal from the first bloodvessel site, wherein the acoustic pressure signal is caused by theabsorption of at least some of the photonic signal by one or moreconstituents at the first blood vessel site, and wherein the acousticpressure signal comprises a thermo-dilution response corresponding to anindicator provided to a second blood vessel site, wherein the indicatoris provided to the second blood vessel site at a temperature differentthan the temperature of the second blood vessel site; and processingequipment configured to determine cardiac output of the subject based onan initial indicator temperature, an initial blood temperature at afirst time, and an adjusted blood temperature at a second time asindicated by the thermo-dilution response and based on an equationhaving the form:${{CO} = \frac{{K\left( {T_{b,0} - T_{i,0}} \right)}V_{i}}{\int{\left( {T_{b,0} - T_{b{(t)}}} \right){\mathbb{d}t}}}},$wherein K is a proportionality constant related to the effects ofspecific gravity and heat capacity of blood, the indicator, or both,T_(b,0) is the initial blood temperature; T_(i,0) is the initialindicator temperature, T_(b(t)) is the adjusted blood temperature, and Vis a volume of the indicator provided to the second blood vessel site.10. The system of claim 9, wherein the processing equipment isconfigured to determine one or more of intrathoracic blood volume,intrathoracic circulatory volume, global end-diastolic volume, pulmonarycirculatory volume, and extravascular lung water based on the cardiacoutput and one or more features of a thermo-dilution curve that isrepresentative of the thermo-dilution response.
 11. The system of claim10, wherein the features comprise a mean transit time of thethermo-dilution curve or a downslope time of the thermo-dilution curve.12. The system of claim 9, wherein the acoustic detector is configuredto detect a hemo-dilution response and the thermo-dilution response. 13.The system of claim 9, wherein the light source configured to provide aphotonic signal to the first blood vessel site is configured to providea photonic signal to an artery of the subject.
 14. The system of claim9, wherein the indicator provided to the second blood vessel site isprovided to a vein of the subject.
 15. The system of claim 9, whereinthe indicator is at least one of a dye indicator and a saline solution.16. The system of claim 9, wherein the processing equipment isconfigured to determine cardiac output based only on: theproportionality constant related to the effects of specific gravity andheat capacity of blood, the indicator, or both; the initial bloodtemperature; the initial indicator temperature; the adjusted bloodtemperature; and the volume of the indicator provided to the secondblood vessel site.
 17. A method for determining a physiologicalparameter of a subject, the method comprising: providing a photonicsignal to a first blood vessel site of the subject; detecting anacoustic pressure signal from the first blood vessel site using one ormore acoustic detectors, wherein the acoustic pressure signal is causedby the absorption of at least some of the photonic signal by one or moreconstituents at the first blood vessel site, and wherein the acousticpressure signal comprises a thermo-dilution response corresponding to anindicator provided to a second blood vessel site, wherein the indicatoris provided at a temperature different than the temperature of thesecond blood vessel site; and determining cardiac output of the subjectbased only on: a proportionality constant related to the effects ofspecific gravity and heat capacity of blood, the indicator, or both; aninitial indicator temperature; an initial blood temperature at a firsttime; an adjusted blood temperature at a second time as indicated by thethermo-dilution response; and a volume of the indicator provided to thesecond blood vessel site.
 18. A method for determining a physiologicalparameter of a subject, the method comprising: providing a photonicsignal to a first blood vessel site of the subject; detecting anacoustic pressure signal from the first blood vessel site using one ormore acoustic detectors, wherein the acoustic pressure signal is causedby the absorption of at least some of the photonic signal by one or moreconstituents at the first blood vessel site, and wherein the acousticpressure signal comprises a thermo-dilution response corresponding to anindicator provided to a second blood vessel site, wherein the indicatoris provided at a temperature different than the temperature of thesecond blood vessel site; determining cardiac output of the subjectbased on an initial indicator temperature, an initial blood temperatureat a first time, and an adjusted blood temperature at a second time asindicated by the thermo-dilution response; and determining one or moreof intrathoracic blood volume, intrathoracic circulatory volume, globalend-diastolic volume, pulmonary circulatory volume, and extravascularlung water based on the cardiac output and one or more features of athermo-dilution curve that is representative of the thermo-dilutionresponse, wherein the features comprise a mean transit time of thethermo-dilution curve or a downslope time of the thermo-dilution curve.19. A system for determining a physiological parameter of a subject, thesystem comprising: a light source configured to provide a photonicsignal to a first blood vessel site of the subject; an acoustic detectorconfigured to detect an acoustic pressure signal from the first bloodvessel site, wherein the acoustic pressure signal is caused by theabsorption of at least some of the photonic signal by one or moreconstituents at the first blood vessel site, and wherein the acousticpressure signal comprises a thermo-dilution response corresponding to anindicator provided to a second blood vessel site, wherein the indicatoris provided to the second blood vessel site at a temperature differentthan the temperature of the second blood vessel site; and processingequipment configured to determine cardiac output of the subject basedonly on: a proportionality constant related to the effects of specificgravity and heat capacity of blood, the indicator, or both; an initialindicator temperature; an initial blood temperature at a first time; anadjusted blood temperature at a second time as indicated by thethermo-dilution response; and a volume of the indicator provided to thesecond blood vessel site.
 20. A system for determining a physiologicalparameter of a subject, the system comprising: a light source configuredto provide a photonic signal to a first blood vessel site of thesubject; an acoustic detector configured to detect an acoustic pressuresignal from the first blood vessel site, wherein the acoustic pressuresignal is caused by the absorption of at least some of the photonicsignal by one or more constituents at the first blood vessel site, andwherein the acoustic pressure signal comprises a thermo-dilutionresponse corresponding to an indicator provided to a second blood vesselsite, wherein the indicator is provided to the second blood vessel siteat a temperature different than the temperature of the second bloodvessel site; and processing equipment configured to: determine cardiacoutput of the subject based on an initial indicator temperature, aninitial blood temperature at a first time, and an adjusted bloodtemperature at a second time as indicated by the thermo-dilutionresponse; and determine one or more of intrathoracic blood volume,intrathoracic circulatory volume, global end-diastolic volume, pulmonarycirculatory volume, and extravascular lung water based on the cardiacoutput and one or more features of a thermo-dilution curve that isrepresentative of the thermo-dilution response, wherein the featurescomprise a mean transit time of the thermo-dilution curve or a downslopetime of the thermo-dilution curve.